This invention relates to an inclusion complex of alprazolam and 2-hydroxypropyl-beta-cyclodextrin, and to pharmaceutical compositions containing such a complex, particularly for oral, nasal or rectal mucosal delivery, for the treatment of anxiety and panic attack.
Alprazolam is also known as 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine.
Alprazolam is indicated for the short term treatment of Generalised Anxiety Disorder (GAD) and has particular utility as an agent for the management of panic disorders (with or without agoraphobia).
In an acute state such as a panic attack, a rapid onset of action is desirable. Although alprazolam is well absorbed from a tablet formulation after conventional orogastric administration, maximum plasma levels occur between 0.7 to 1.8 hours post-dose. The onset of anxiolysis correlates with attainment of maximum plasma levels. The absorption rate is therefore often not sufficiently rapid to provide immediate symptomatic relief in an anxiety crisis.
Absorption of alprazolam from the stomach is further adversely affected by the presence of food and antacids, the use of the latter being frequently associated with stress related syndromes. Rapid absorption of alprazolam in a manner which would avoid these complications and avoid the need for administration of the dosage form with a liquid would have distinct advantages.
The mucosal route of drug delivery, in particular the sublingual or nasal mucosal routes, offer a useful alternative to parenteral delivery where a rapid therapeutic effect is desired. Sublingual use of the commercially available oral tablet dosage forms of alprazolam offers no significant benefit over conventional orogastric administration in terms of speed of onset [see J. M. Scavone etal, J. Clin. Psychopharmacol., 1987, 7, 332–335]. Formulation of alprazolam in a manner which permits rapid uptake from the sublingual, nasal or rectal mucosa would have distinct utility in the emergency relief of anxiety symptoms.
The oral, nasal and rectal cavities have several advantages as sites for systemic drug delivery, particularly avoidance of pre-systemic metabolism.
However, the low permeability of the membranes that line the oral and nasal cavities result in a low flux of drug. There is therefore a need to enhance drug solubility and penetration to improve bioavailability following oral or nasal mucosal drug delivery.
There are several methods known in the art to deliver drugs to the oral, nasal and rectal mucosae. These include buccal and sublingual tablets or lozenges, adhesive patches, gels, solutions or sprays (powder, liquid or aerosol) for the oral cavity and solutions or sprays (powder, liquid or aerosol) for the nasal cavity and suppositories for rectal administration.
The absorption of drugs from mucosal membranes may be enhanced by (i) increasing drug solubility, (ii) pH modification to favour the unionised form of the drug, (iii) addition of mucoadhesive agents to improve contact between the delivery system and the membrane and (iv) incorporation of so-called penetration enhancers.
There are a number of penetration enhancers known to influence the permeability of drugs across epithelial membranes (for a recent review see Walker, R. B. and Smith, E. W. Advanced Drug Delivery Reviews 1996, 18, 295–301).
Cyclodextrins and their derivatives have found extensive application as solubilizers and stabilizers due to their ability to form inclusion complexes with a wide variety of compounds (see J. Szejtli, Cyclodextrin Technology, Kluwer Academic Press) and (J. Szejtli & K-H Fromming, Cyclodextrins in Pharmacy, Kluwer Academic Press).
Cyclodextrins have been used to enhance intestinal absorption of drugs primarily through increasing solubility. Recently, cyclodextrins have been shown to have positive and negative effects on transdermal penetration of drugs (see Loftsson, T. et al. International Journal of Pharmaceutics 1995, 115, 255–258), (Vollmer, U. et al. International Journal of Pharmaceutics 1993, 99, 51–58), (Legendre, J. Y. et al. European Journal of Pharmaceutics 1995, 3, 311–322) and (Vollmer, U. et al Journal of Pharmacy and Pharmacology 1994, 46, 19–22). Cyclodextrins may improve nasal absorption of drugs (see Merkus, F. W. et al. Pharmaceutical Research 1992, 9, 1157–1163) and enhance absorption from sublingual administration of drug/cyclodextrin complexes. Cyclodextrins also protect nasal mucosal damage by penetration enhancers (see Jabbal. Gill, I. et al. European Journal of Pharmaceutical Sciences 1994, 1 (5), 229–236).
Cyclodextrins are water soluble cone-shaped cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units. The interior “cavity” of the cone is hydrophobic whilst the exterior is hydrophilic. The size of the cavity increases with increasing number of glucose units. Several cyclodextrin derivatives such as alkyl, hydroxyalkyl and sulfoalkyl ethers have been prepared with improved solubility (see J. Szejtli & K-H Fromming, Cyclodextrins in Pharmacy, Kluwer Academic Press) and (Stella, V. J. et al. Pharmaceutical Research 1995, 12 (9) S205). Suitably sized hydrophobic “guest” molecules may enter the “host” cavity to form a classical host-guest “inclusion compound” or “inclusion complex” with either the entire guest molecule included or only a portion thereof. The driving mechanism for cyclodextrin inclusion complexation is the affinity of the hydrophobic guest molecule for the cavity of the cyclodextrin host molecule with displacement of cavity water molecules to a thermodynamically more stable state. The term “complex stability” or stability of a given inclusion complex refers to the association/dissociation equilibrium of host and guest in solution. Complex stability depends on the number of intermolecular bonding interactions between the host and guest. Van der Waals forces and hydrophobic interactions are the main interactions stabilising inclusion complexes (Bergeron, R. J. et al. Journal of the American Chemical Society 1977, 99, 5146). Depending on the nature and position of hydrogen bonding functionalities on a given guest, there may be hydrogen bonding between the guest and hydroxyl groups of the cyclodextrin or other hydrogen bonding groups in the case of cyclodextrin derivatives. Ionic interactions between the host and guest are also possible in the case of ionic cyclodextrins such as sulfobutyl ethers (Stella, V. J. et al. Pharmaceutical Research 1995, 12 (9), S205).
Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components (J. Szejtli, Cyclodextrin Technology, Kluwer Academic Press). The first is accomplished by dissolving the cyclodextrin and guest in a suitable solvent or mixture of solvents and subsequently isolating the solid state complex by crystallisation, evaporation, spray drying or freeze drying. In the solid state method, the two components may be screened to uniform particle size and thoroughly mixed whereafter they are ground in a high energy mill with optional heating, screened and homogenised. In the semi-solid state, the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is dried, screened and homogenised.
The liquid state reaction generally provides optimum conditions for completeness of reaction. Depending on solvent conditions, the dissolved inclusion complex exists in equilibrium between uncomplexed host and guest and complexed host/guest.
The use of cyclodextrins to increase the solubility of alprazolam has been described. In an article in Acta Pharm. Nord. 3 (4), 1991, 215–217, Loftsson et al describe the effect of the cyclodextrin derivative, 2-hydroxypropyl-beta-cyclodextrin, on the aqueous solubility of 13 different drugs, including alprazolam. A 16-fold solubility enhancement for alprazolam in a 20% solution of 2-hydroxypropyl-beta-cyclodextrin is reported. No solid complex is described.
In a subsequent article published in Int. J. Pharm, 1994, 110, 169–177, Loftsson et al describe the effect of 2-hydroxypropyl-beta-cyclodextrin on the water solubility of alprazolam in the presence and absence of water soluble polymers. Enhanced solubility of alprazolam is obtained following heating of a solution of 2-hydroxypropyl-beta-cyclodextrin and a water soluble polymer in a sealed container at 120° C. for 20 minutes. No solid complex is described.
JP 07165616 to Hisamitsu Pharmaceutical Company, Japan similarly claims the formation of inclusion complexes of drugs with cyclodextrin in the presence of water soluble polymers to improve solubility and stability.
Loftsson et al [see Int. J. Pharm, 1998, 162 (2), 115–121] have also reported an enhancement in the solubility and have demonstrated improved complexing ability for beta-cyclodextrin in solutions of drugs containing water soluble polymers, including the drug alprazolam. No solid complex is described.
DE 44 28 986 A1 to KRKA, Slovenia teaches the formulation of rapidly dissolving solid dosage forms for orogastric administration of alprazolam containing alpha-, beta-, or gamma cyclodextrin when employed as water soluble carriers. Alprazolam is deposited on the carrier by spray drying prior to incorporation into a tablet.
U.S. Pat. Nos. 5,288,497 and 5,785,989 to Stanley, T. H. et al (The University of Utah) entitled “Compositions of Oral Dissolvable Medicaments” and “Compositions and Methods of Manufacturing of Oral Dissolvable Medicaments”, respectively, recite in their claims a drug-containing dosage form (where the drug is a benzodiazepine) which permits absorption through the mucosal tissues of the mouth. The dosage form is referred to as an “appliance or holder” containing drug dispersed into a carbohydrate, fat, protein, wax or other dissolvable matrix.
In WO 99/42111, Loftsson et al. discuss methods for enhancing cyclodextrin complexation. Loftsson et al deemed it necessary to increase the aqueous solubility and complexation efficiency of the alprazolam by lowering the pH to below 5 in order to formulate alprazolam as a successful formulation for transmucosal delivery. A first drawback of such a formulation with a pH of lower than 5 for transmucosal delivery of an active ingredient is that the lower pH may result in mucosal irritation causing increased saliva production, adversely affecting oral transmucosal drug delivery, thereby decreasing the patient's compliance due to oral mucosal irritation. A formulation causing oral mucosal irritation will increase saliva production, decreasing the efficacy of the sublingual formulation, due to increased swallowing of the alprazolam-cyclodextrin complex. A second drawback is that, in use, the presence of alprazolam ring-open form will in fact negatively influence transport across mucosal membranes since it is well established that absorption of drugs across mucosal membranes is enhanced by favouring the unionised (or ring-closed) form (Rathbone, et al. 1996. Systemic oral mucosal drug delivery and delivery systems, In. Oral mucosal drug delivery, Marcel Dekker:New York, p. 253).